Defibrillation is now recognized as the only effective means to prevent sudden cardiac death, and implantable cardioverter-defibrillators have been shown to improve survival in high risk individuals. Nevertheless, the high voltage shocks from these devices are associated with a host of adverse effects, including increased incidence of heart failure, abnormal rhythms, cellular and tissue dysfunction, significant skeletal muscle stimulation, and pain. Modifications to the shock waveforms and novel electrode systems have met with limited success in avoiding these problems. This project will utilize a novel approach to defibrillate the heart by a completely different mechanism than what occurs with conventional defibrillation. Our central hypothesis, borne out by preliminary data, is that in response to an external alternating electric field in the kHz range, the transmembrane voltage of cardiac cells becomes trapped at a partially elevated potential and is held in a refractory state. This state completely blocks impulse propagation and can reliably terminate reentrant arrhythmias such as fibrillation. Our approach may represent an enormous advance because skeletal muscle and nerves may be similarly unable to activate during the HF field, reducing or eliminating the pain associated with defibrillation. Furthermore, because defibrillation is the result of propagation block, device testing will no longer require induction and termination of ventricular fibrillation, as propagation block can be assessed during normal or paced rhythm. The specific aims of this project are: (1) to optimize the waveform parameters to block impulse propagation and terminate arrhythmia by persistently depolarizing cardiac cells without evoking repetitive activity, and (2) to test the hypothesis that HF stimulation will inhibit myocardial impulse propagation and terminate fibrillation in an intact mammalian heart. These ideas will be tested using a three-prong approach consisting of (a) detailed, biophysical studies in an in vitro cell monolayer model;(b) computational tissue models of different mammalian species, including human, that will provide mechanistic insight, and (c) experiments in the intact pig to compare efficacy of HF defibrillation with conventional defibrillation and to determine whether HF stimulation provokes induction of arrhythmias and skeletal muscle activation. In summary, the proposed research will evaluate the efficacy of high frequency field stimulation as a novel form of electrical therapy that can block cardiac impulse propagation and terminate arrhythmia, with minimal adverse cardiac effects and reduced pain. The results from this basic work have the potential to translate directly into clinical practice by revolutionizing arrhythmia management. PUBLIC HEALTH RELEVANCE: Defibrillation is now recognized as the only effective means to prevent sudden cardiac death, and implantable devices have been shown to improve survival in high risk individuals. Nevertheless, high voltage shocks delivered by present-day defibrillators are associated with a host of adverse effects, including increased incidence of heart failure, abnormal cardiac rhythms, damage to the heart, and pain. The goal of this project is to determine whether a novel approach for arrhythmia termination that we have discovered translates into more effective defibrillation together with a reduction of heart damage, pain, and ensuing psychological trauma widely associated with defibrillation shocks.